Our immune response is critical to our ability to fight bacterial and viral infections.  It is controlled by a large number of proteins which are found on the surface of cells that circulate in the blood called T cells, B cells, macrophages and platelets.  Some of these cell surface proteins are directly involved in the recognition of products produced by bacteria and viruses and their elimination from the body.  However, this cannot happen without the help of co-stimulatory and co-inhibitory molecules which can promote or suppress immune cell activation. 

After engagement of the T cell receptor it is well accepted that binding of CD80/CD86 to CD28 provides major co-stimulatory signals for T cell activation and functional differentiation, while binding to CTLA4 (CD152) provides a signal for the termination of activation and cellular function of T cells.  However, other receptors also contribute to these events including ICOS and its ligand ICOSL, PD-1 and its ligands PD-L1 and PD-L2, and BTLA and its ligand HVEM.  The downstream propagation of activation signals in B cells through CD40 and CD19/CD21/CD81 is attenuated by a number of co-inhibitory receptors such as PIR-B, CD22 and CD32. 

The growing number of T and B cell co-signalling receptors and the dynamic nature of the immune response indicate that there might be a hierarchy of co-stimulatory and co-inhibitory receptors for regulating the responses of naïve, effector and memory T and B cells.  Clearly, the balance of stimulatory and inhibitory signals is crucial to maximise protective immune responses while maintaining immunological tolerance and preventing autoimmunity, and emphasises the need to have a clear understanding of the roles of all co-signalling receptors in these processes.

Unfortunately, sometimes the immune system gets out of control and begins to attack one’s own tissue.  The results of this are conditions called autoimmune diseases, common examples of which are Type 1 Diabetes and Rheumatoid Arthritis (RA).  However, from much research over the last 20 years it is clear that not everyone in the population suffers from autoimmune diseases even though we all have the same cell surface proteins.  This means that there must be differences in these proteins in the population, either due to differences in the protein sequence or to differences in the levels of the proteins on the cell surface.

A large number of genetic studies have identified the Major Histocompatibility Complex (MHC) on human chromosome 6 as playing a key role in autoimmune disease susceptibility.  However, although the human MHC has been sequenced and fully annotated it has still proved very difficult to identify exactly which genes are involved in autoimmune disease susceptibility.

Current Research Programme

We have identified a cluster of four genes (G6B, G6F, LY6G6C and LY6G6D), lying adjacent to one another in a segment of the MHC strongly associated with susceptibility to RA that are of major interest as they encode novel cell surface molecules.  Our initial functional characterisation of G6B, which is expressed in platelets, indicates that it could be a new member of the family of co-inhibitory receptors while G6F, which is also expressed in platelets, could be a novel co-stimulatory receptor involved in cellular activation.  We are carrying out a thorough transcriptional and functional analysis of G6B, G6F, LY6G6C and LY6G6D, to establish where the proteins are expressed, what controls their expression, and what cellular ligands they bind to. 

Novel receptor-ligand interactions are being characterised further using BIAcore analysis.  The functional consequences of polymorphisms that affect coding sequences, as well as those that might affect expression of the genes, are being elucidated.  The data will provide a strong foundation for further investigations of the receptors and the cell types they are expressed on in the context of their involvement in autoimmune disease susceptibility.

Duncan Campbell